1. Field of the Invention
The present invention generally relates to formulations for use in Metered Dose Inhalers and, more particularly, to improved formulations with reduced ozone-depletion and global warming potentials.
2. Description of the Prior Art
Metered-dose inhalers (MDIs) are a well-known form of treatment for numerous respiratory conditions. MDIs comprise a pressure resistant container fitted with a metering valve. The container is filled with a medicament, such as a bronchodilator or corticosteroid, which is dissolved or suspended in a liquified propellant. Actuation of the metering valve allows a small portion of the spray product to be released, whereby the pressure of the liquified propellant carries the drug particles out of the container to the patient. The valve actuator is used to direct the aerosol spray into the patient's mouth.
Typically the liquefied propellants comprise 70-99 wt % of the formulation and, heretofore, have generally been chlorofluorocarbons (CFCs) or blends of two or more CFCs, such as trichlorofluoromethane (CCl.sub.3 F or CFC-11), dichlorodifluoromethane (CCl.sub.2 F.sub.2 or CFC-12, and 1,2-dichloro-1,1,2,2-tetrafluoroethane (CClF.sub.2 --CClF.sub.2 or CFC-114). CFC propellants are ideal for use in MDIs because they exhibit low toxicity, chemical stability and high purity. Recently, however, the use of CFCs has come under sharp attack because their high resistance to degradation, which is a desirable property in MDI formulations, also allows CFCs to persist in the atmosphere and thereby cause considerable ozone-depletion and global-warming. Signatory countries to the Montreal Protocol on Substances That Deplete the Ozone Layer have now begun to implement the agreed-upon control measures on CFCs which require progressively decreasing production of CFCs culminating in their complete ban by the year 2,000 a.d.
Hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs), hydrocarbons (HCs) and other propellants such as dimethylether (DME) are now being considered as replacements for CFCs. CFCs are alkyl molecules with chloro and fluoro moieties on the carbon backbone. HCFCs differ from CFCs in that they contain one or more hydrogen atoms per molecule, which makes them less chemically stable than CFCs. HCFCs often have low vapor pressures at ambient temperature, which is not desirable in MDIs. However, their ozone-depletion and global-warming potentials are significantly lower than those of CFCs. HFCs contain no chlorine and, therefore, have no ozone-depletion potential. They are generally nonflammable, but are poorer solvents than HCFCs or CFCs. The global-warming potential of HFCs is similar to that of HCFCs. HCs lack toxicity, are low in cost, and have an infinitely variable vapor pressure between 31 and 125 psia. Their major disadvantages are considered to be their flammability and low liquid density.
There are two types of formulations administered using MDIs: solutions and suspensions. In conventional solution-type MDIs, a drug is dissolved with the aid of non-volatile cosolvents such as ethanol. In suspension formulations, small micronized particles of undissolved drug are distributed in the propellant blend. A common suspension formulation which is administered to asthmatics contains the drug beclomethasone diproprionate (BDP). When BDP is dissolved in a mixture of CFCs containing CFC-11, rapid crystal growth occurs. This has been attributed to an association between BDP and CFC-11 known as a "clathrate". If large crystals are permitted to form in an MDI, then, upon inhalation, the particles will impact the oropharynx rather than the bronchioles or pulmonary regions of the lung where they are required to exert their therapeutic effects. Large particles may also disrupt the operation of the metering valve. These problems have been overcome in some prior art CFC formulations by using a method of preswelling BDP particles by exposure to CFC-11 to form the clathrate, then remicronizing to produce small particles which are mixed with the other aerosol formulation ingredients.